October 2025

Melatonin in Cancer Therapy

Joseph Corsini, Ph.D. and Julie Alessandra, MTE

Melatonin is an evolutionarily ancient molecule found throughout the living world, from bacteria and fungi to plants to worms to humans (reviewed in Zhao et al 2019). The body makes melatonin in two primary ways, both reliant on natural light. The first is related to the light signaling pathways of the pineal gland. In that pathway, melatonin is synthesized in pinealocytes (cells of the pineal gland) through the sequential action of four enzymes, two of which convert the amino acid tryptophan into 5-hydroxy tryptophan and then to serotonin during the day, and two of which convert serotonin into melatonin after nightfall (Barbosa et al 2008; Lee et al 2021; Wang et al 2024) for release into circulation. This process leads to the production of around 5% of the body’s melatonin. The second way (which generates the remaining 95% of melatonin) is related to the antioxidant duties of melatonin. In this process, melatonin produced by the mitochondria in cells in the body in the presence of infrared light (half of the electromagnetic radiation from the sun is invisible infrared light). Most people are deficient in melatonin because they do not receive enough natural light exposure and are exposed to artificial light at night, especially blue light wavelengths after sunset which destroy melatonin stores.

Because melatonin functions primarily as an antioxidant, it is thought to have been originally invented by evolution to function as a free-radical scavenger as oxygen produced by the first photosynthetic cyanobacteria accumulated in the atmosphere. Through the eons, it has been repurposed by evolution into an important signal molecule with its own dedicated cellular receptor called MT - in mammals there are two versions of the receptor, MT1 and MT2 (see Jockers 2016 for a review). These receptors are expressed by many cell types in the body and are directly involved with the light signaling pathways of the pineal gland that modulate our daily circadian cycles. While the pineal melatonin is clearly important for sleep cycles and overall health, it is the melatonin produced by cells (so called subcellular or endogenous melatonin) in response to oxidative stress in the mitochondrion that has a more direct bearing on cancer (the connection between mitochondria and cancer will be reviewed in an accompanying informational bulletin).

Two decades of study have provided us with mounting evidence that supplemental melatonin has a number of anti-tumor activities when co-administered with primary treatment or as an adjuvant (a treatment that is administered after the primary therapy). Investigations into the use of supplemental melatonin have been extensively reviewed by Proietti and colleagues (2017), as well as by Li et al (2017), Talib et al (2021), and Reiter et al (2024). Pre-clinical work suggests that melatonin might have anti-tumor effects on certain cancers. For example, Jardim-Perassi et al (2014) demonstrated that exogenous melatonin reduces progression of transplanted human breast cancer tumors in nude mouse models. In that work they noted that tumor progression was blocked by a lack of angiogenesis (blood vessel formation). Other studies with ovarian cancer in rats have also shown that melatonin reduces tumor growth (Chuffa et al 2013). In a human trial, Lissoni and colleagues (1999) administered melatonin to 250 individuals with metastatic solid tumors including breast cancer, lung cancer, and head/neck cancer. The authors observed significant improvements in one-year survival rates and tumor regression, and noted significant decreases in toxic effects from the chemotherapy (including neurotoxicity and cardiotoxicity). While often not well-controlled, other studies at the Di Bella Institute administering therapeutic doses of melatonin, vitamin D, somatostatin, and retinoids (see Di Bella 2011 and reviewed in Reiter 2024) also suggest melatonin can be used safely as part of treatment cocktails that lead to improvements in long term survival of late-stage cancers. Alsheri and Althobaity (2024) review human clinical trials, noting that while some studies demonstrate positive effects of melatonin on cancer outcomes, others show no effect. They conclude that, while promising as a therapy, dosing and other systematic aspects of melatonin use in cancer treatment have yet to be determined. While the anti-tumor mechanisms of melatonin have not been clearly elucidated, evidence suggests that modulation of mitochondrial apoptotic (cell suicide) pathways and antiangiogenic effects are at least partly responsible for these activities. It is important to note that an exception to the antitumor effects of melatonin may be gastric (stomach) cancer, where there is some evidence that supplemental melatonin actually induces angiogenesis in those cancers (see review by Ma et al 2019). In addition, adverse interactions have been reported with melatonin in combination with the ribociclib (Kisqali) family of chemotherapeutic agents.  

Comment on Quality Control of Melatonin Supplements: Melatonin is a hormone that is made naturally in your body, but it can also be obtained from many dietary sources, with higher concentrations in eggs, fish, nuts, germinated legumes, and some types of mushrooms (Meng et al 2017). Melatonin supplements are very commonly used, and appear to be well-tolerated. We do note that melatonin is not an FDA approved drug, and that quality control issues are common in the melatonin supply. These issues are exemplified in a 2017 study by Erland and colleagues that used ultraperformance liquid chromatography to analyze melatonin from 31 suppliers. 71% of the supplement lots were off on the concentration by more than 10%, with one off by -83% and another by +465%.  Furthermore, many of the products also contained significant levels of serotonin, which as a neurotransmitter is regulated because of its neurotropic effects and potential toxicity.

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